Renin is the main determinant of angiotensin (Ang) II levels. It, therefore, always appeared desirable to reduce Ang II levels by direct inhibition of renin. So far, specific renin inhibitors lacked potency and/or oral availability. We tested the new orally active nonpeptidic renin inhibitor SPP100 (Aliskiren, an octanamide with a 50% inhibitory concentration [IC50] in the low nanomolar range) in 18 healthy volunteers on a constant 100 mmol/d sodium diet using a double-blind, 3-way crossover protocol. In 3 periods of 8 days, separated by wash-outs of 6 days, each volunteer received 2 dosage levels of Aliskiren (low before high; 40 and 80 or 160 and 640 mg/d) and randomized placebo or 20 mg enalapril. Aliskiren was well tolerated. Not surprisingly, blood pressure and heart rate remained unchanged in these normotensive subjects. There was a dose-dependent decrease in plasma renin activity, Ang I, and Ang II following single doses of Aliskiren starting with 40 mg. Inhibition was still marked and significant after repeated dosing with maximal decreases in Ang II levels by 89% and 75% on Days 1 and 8, respectively, when the highest dose of Aliskiren was compared with placebo. At the same time, mean plasma active renin was increased 16- and 34-fold at the highest dose of Aliskiren. Plasma drug levels of Aliskiren were dose-dependent with maximal concentrations reached between 3 to 6 hours after administration; steady state was reached between 5 and 8 days after multiple dosing. Less than 1% of dose was excreted in the urine. Plasma and urinary aldosterone levels were decreased after doses of Aliskiren > or =80 mg and after enalapril. Aliskiren at 160 and 640 mg enhanced natriuresis on Day 1 by +45% and +62%, respectively, compared with placebo (100%, ie, 87+/-11 mmol/24h) and enalapril (+54%); kaliuresis remained unchanged. In conclusion, the renin inhibitor Aliskiren dose-dependently decreases Ang II levels in humans following oral administration. The effect is long-lasting and, at a dose of 160 mg, is equivalent to that of 20 mg enalapril. Aliskiren has the potential to become the first orally active renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in therapy for hypertension and other cardiovascular and renal diseases.